Compositions and methods of treatment comprising amoxicillin and potassium clavulante with xanthan

ABSTRACT

Bacterial infections may be treated using a high dosage regimen of amoxicillin and potassium clavulanate. Preferably, the dosage is provided by a bilayer tablet.

FIELD OF THE INVENTION

This invention relates to a novel method of treatment using amoxicillinand potassium clavulanate and for novel formulations, in particulartablet formulations, for use in such methods.

BACKGROUND OF THE INVENTION

Amoxicillin and potassium clavulanate are respectively a known β-lactamantibiotic and a known β-lactamase inhibitor. Products comprisingamoxicillin and potassium clavulanate are marketed under the trade name“Augmentin” by SmithKline Beecham. Such products are particularlyeffective for treatment of community acquired infections, in particularupper respiratory tract infections in adults and otitis media inchildren.

Various tablet formulations of amoxicillin and potassium clavulanatehave been approved for marketing, comprising various different weightsand ratios of amoxicillin and potassium clavulanate, for instance,conventional swallow tablets comprising 250/125, 500/125, 500/62.5, and875/125 mg amoxicillin/clavulanic acid (in the form of potassiumclavulanate). Such tablets comprise amoxicillin and clavulanic acid inthe ratio 2:1, 4:1, 8:1 and 7:1, respectively. The 875/125 mg tablet wasdeveloped to provide a tablet formulation which could be administered ina bid (twice daily) dosage regimen It is also marketed for tid (threetimes daily) dosing, in Italy and Spain. The 500/62.5 mg tablet was alsodeveloped to provide a tablet formulation which could be administered ina bid dosage regimen, two such tablets being taken every 12h, inpreference to a single 1000/125 mg tablet. A 1000/125 mg single dosageis also available, in France, but as a single dosage sachet rather thana tablet. Typically, the approved regimens provides a single dosage of125 mg of potassium clavulanate.

In addition, WO 97/09042 (SmithKline Beecham) describes tabletformulations comprising amoxicillin and clavulanic acid in a ratio inthe range 12:1 to 20: 1, preferably 14:1. Furthermore, it is suggestedthat the preferred dosage of 1750/125 mg may be provided as two tablets,the first comprising 875/125 mg amoxicillin and clavulanic acid and thesecond 875 mg amoxicillin. The 14:1 ratio is said to be useful for theempiric treatment of bacterial infection potentially caused by drugresistant S pneumoniae (DRSP). This patent application also describespaediatric formulations comprising amoxicillin and clavulanate in a 14:1ratio, for administering amoxicillin dosages of 90 mg/kg/day. Datasuggest that such a dosage may provide antibiotic concentrationssufficient to eradicate DRSP with amoxicillin+/−clavulanic acid MICs ≦4μg/ml (Bottenfield et al, Pediatr Infect Dis J, 1998, 17, 963-8).

WO 94/16696 (SmithKline Beecham) discloses generally that clavulanicacid may unexpectedly enhance the efficacy of amoxicillin againstmicroorganisms having a resistant mechanism which is not β-lactamasemediated.

Existing marketed tablet formulations of amoxicillin and potassiumclavulanate are conventional in that they provide immediate release ofthe active ingredients once the tablet reaches the stomach. There hasalso been some interest in developing formulations in which the releaseprofile is modified, to allow for a longer interval between dosages, forinstances, every 12 hours (bid, q12 h), rather than every 8 hours (tid,q8 h).

Thus, for instance, WO 95/20946 (SmithKline Beecham) describes layeredtablets comprising amoxicillin and, optionally, potassium clavulanate,having a first layer which is an immediate release layer and a secondlayer which is a slow release layer. The broadest ratio of amoxicillinto clavulanic acid is 30:1 to 1: 1, with a preferred range of 8:1 to1:1. Amoxicillin is suitably in the form of amoxicillin trihydrate.Examples provided of such bilayered tablets have amoxicillin trihydratein the immediate release layer and amoxicillin plus clavulanate in theslow release layer. Multi-layered tablets are described more genericallyin WO 94/06416 (Jagotec AG). Further bilayered tablets comprisingclavulanic acid and amoxicillin are described in WO 98/05305 (QuadrantHoldings Ltd). In such tablets, a first layer comprises amoxicillin anda second layer comprises clavulanate and the excipient trehalose, tostabilise the clavulanate component.

In addition, WO 95/28148 (SmithKline Beecham) describesamoxicillin/potassium clavulanate tablet formulations having a corecontaining amoxicillin and potassium clavulanate coated with a releaseretarding agent and surrounded by an outer casing layer of amoxicillinand potassium clavulanate. The release retarding agent is an entericcoating, so that there is an immediate release of the contents of theouter core, followed by a second phase from the core which is delayeduntil the core reaches the intestine. Furthermore, WO 96/04908(SmithKline Beecham) describes amoxicillin/potassium clavulanate tabletformulations which comprise amoxicillin and potassium clavulanate in amatrix, for immediate release, and granules in a delayed release formcomprising amoxicillin and potassium clavulanate. Such granules arecoated with an enteric coating, so release is delayed until the granulesreach the intestine. WO 96/04908 (SmithKline Beecham) describesamoxicillin/potassium clavulanate delayed or sustained releaseformulations formed from granules which have a core comprisingamoxicillin and potassium clavulanate, surrounded by a layer comprisingamoxicillin. WO 94/27557 (SmithKline Beecham) describes controlledrelease formulations of amoxicillin and clavulanic acid prepared using ahydrophobic waxy material which is then subjected to thermal infusion.

Controlled release formulations comprising amoxicillin have beendescribed by several groups. Thus, Arancibia et al ((Int J of ClinPharm, Ther and Tox, 1987, 25, 97-100) describe the pharmacokineticproperties and bioavailability of a controlled release formulationcomprising 500 mg of amoxicillin. No further details of the formulationare provided. The formulation was however designed to release 21 to 35%during the first 60 minutes, 51 to 66% at 4 hours, 70 to 80% at 6 hours,81 to 90% at 8 hours and more than 94% at 12 hours. They however foundlittle, if any, correlation between the in vitro dissolution rate andthe pharmacokinetic behaviour in the body. Hilton et al (InternationalJournal of Pharmaceutics, 1992, 86, 79-88) described an alternativecontrolled release tablet having a hydrophilic polymer matrix and a gasrelease system, to provide intragastric buoyancy, to enhance gastricretention time. This showed no advantage over a conventional capsuleformulation, with bioavailability being diminished. In contrast, Hiltonet al (Journal of Pharmaceutical Sciences, 1993, 82, 737-743) describeda 750 mg controlled release tablet incorporating the enteric polymerhydroxypropylmethyl cellulose acetate succinate. This however failed toshow any advantage over a conventional capsule. In particular, thebioavailability was reduced to 64.6% compared with the same dosageprovided in a capsule. More recently, Hoffman et al (Journal ofControlled Release, 1998, 54, 29-37 and WO 98/22091) have described atablet comprising 500 mg of amoxicillin in a matrix comprisinghydroxypropyl methyl cellulose, designed to release 50% of its contentsin the first three hours and complete the drug release process overeight hours. The time above MIC was found to be significantly extended,compared to a capsule formulation, but not enough for a 12 h dosinginterval. The discussion is in the context of a theoretical MIC of 0.2μg/ml.

It has therefore, been determined that there is a continuing need toprovide new dosage regimens for amoxicillin/clavulanate which areeffective against more resistant bacteria.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating bacterialinfections in humans which comprises administering thereto atherapeutically effective amount of amoxicillin and potassiumclavulanate such that the amount of amoxicillin is in the range 1900 to2600 mg and the amount of potassium clavulanate is such that the weightratio of amoxicillin to clavulanate is from about 2:1 to 20: 1, an at adosage regiment/interval of about 12 hours. Suitably, the infection iscaused by the organisms S pneumoniae (including Drug Resistant andPenicillin Resistant S pneumoniae), H influenzae and/or M catarrhalis.

The present invention also relates to a modified release pharmaceuticalformulation comprising amoxicillin and potassium clavulanate in theratio from 2:1 to 20:1 in which all of the potassium clavulanate and afirst part of amoxicillin are formulated with pharmaceuticallyacceptable excipients which allow for immediate release of the potassiumclavulanate and the first part of amoxicillin, to form an immediaterelease phase, and further comprising a second part of amoxicillinformulated with pharmaceutically acceptable excipients which allow forslow release of the second part of amoxicillin, to form a slow releasephase.

The present invention also relates to an immediate releasepharmaceutical tablet formulation comprising 1000 mg±5% amoxicillin and62.5 mg±5% potassium clavulanate, in a nominal ratio of about 16:1, incombination with pharmaceutically acceptable excipients or carriers.

The present invention also relates to an immediate releasepharmaceutical formulation in the form of a single dose sachetcomprising 2000, 2250 or 2500 mg±5% amoxicillin and 125 mg±5% potassiumclavulanate, in a nominal ratio of about 16:1, 18:1 or 20:1,respectively, or the corresponding half quantities thereof, incombination with pharmaceutically acceptable excipients or carriers.

Other suitable modified or immediate release formulations are describedherein in greater detail.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structure of various types of layered tablets of thepresent invention, in particular the structure of substantiallycylindrical compressed tablets are shown in longitudinal section. In

FIG. 1A, shows a tablet comprising a first layer (1) and a second layer(2), without any barrier layer or coating layer.

FIG. 1B, shows a tablet comprising a first layer (1), a second layer(2), and a barrier layer (3) sandwiched between the first and secondlayers (1) and (2).

FIG. 1C, shows a tablet comprising a first layer (1), a second layer(2), and a barrier layer (3) located on the end face of the second layer(2).

FIG. 1D, shows a tablet comprising a first layer (1), a second layer(2), a barrier layer (3) sandwiched between the first and second layers(1) and (2), and a coating layer (4) which partly covers the tablet. Thedotted line shows the possibility of the coating layer (4A) covering theentire tablet.

FIG, 1E, shows a tablet comprising a first layer (1) a second layer (2),and a third layer (3) intermediate between the first and second layers(1) and (2). All three of these layers (1), (2) and (3) include activematerial content.

FIG. 2 demonstrates modified release tablets prepared according to theprocess flow diagram shown in FIG. 2. In brief, immediate and modifiedrelease blends are prepared which involve initial sieving and milling,as indicated, before roller compaction in a Chilsonater and furthermilling, sieving and blending.

FIG. 3 demonstrates the dissolution profile for tablets of Examples 1and 2.

FIG. 4 demonstrate the pharmacokinetic profiles of Study A

FIG. 5 demonstrates the pharmacokinetic profile for amoxicillin plasmaconcentration for Study B (in which A is formulation V, B is formulationVI, D is formulation VIII).

DETAILED DESCRIPTION OF THE INVENTION

Part of the challenge in providing formulations of amoxicillin in whichthe drug release is effectively modified (and a ready explanation forthe lack of success in the studies already referenced) is the relativelynarrow window for absorption of the drug in the small intestine and therelatively short half life of the drug. Furthermore, the rapidelimination of amoxicillin (excretion half-life is 1.3 hours) makes itdifficult to maintain serum levels as clearance from the body is veryrapid.

In existing tablet formulations comprising amoxicillin and potassiumclavulanate, amoxicillin is present in the form amoxicillin trihydrate,as the use of this form provides tablets with greater storage stabilitythan those in which amoxicillin is present as sodium amoxicillin (see GB2 005 538, Beecham Group Ltd). Sodium amoxicillin is however used as theamoxicillin component in existing formulations of amoxicillin andpotassium clavulanate adapted for IV administration. The form of sodiumamoxicillin used is a spray-dried form. In addition, EP 0 131 147-A1(Beecham Group plc) describes a further form of sodium amoxicillin,so-called “crystalline sodium amoxicillin”. A further process forpreparing salts of amoxicillin, including sodium amoxicillin, isdescribed in WO 99/62910 (SmithKline Beecham). Sodium amoxicillin isrelatively water soluble in comparison to amoxicillin trihydrate.

Formulations comprising clavulanic acid and a pharmaceuticallyacceptable organic acid or a salt-like derivative thereof, for examplecalcium citrate, have been described in WO 96/07408 (SmithKlineBeecham). In such formulations, it is postulated that the presence ofthe calcium citrate would help suppress the gastro-intestinalintolerance associated with oral dosing of clavulanate-containingproducts.

Furthermore, U.S. Pat. No. 5,051,262 (Elan Corp) describes theincorporation of an organic acid into a modified release formulation, toprovide a microenvironment in which the locally modified pH helps toprotect the active ingredient from degradation.

Of concern is the increasing resistance of pathogenic organisms, such asthose found in respiratory tract infections, to anti-infective agentssuch as amoxicillin/potassium clavulanate, in particular drug resistantS pneumoniae. Increased resistance to penicillin of S pneumoniae (due tomodified penicillin binding proteins) is developing around the world andis affecting clinical outcomes (see for instance Applebaum P C, Ped InfDis J, 1996, 15 (10), 932-9). These penicillin resistant S pneumoniae(PRSP) have also been termed “DRSP” as they often exhibit decreasedsusceptibility not only to penicillin but also to a wider range ofantimicrobial classes, including macrolides, azalides, beta-lactams,sulfonamides and tetracyclines. Amoxicillin (with or withoutclavulanate), along with some of the newer quinolones, has remainedamong the most active oral drugs against the increasingly resistantisolates of S pneumoniae, based on both MIC levels and pharmacokineticproperties of these compounds. Resistance rates (and MICs) have howevercontinued to increase. Penicillin resistance in S. pneumoniae can beassessed according to criteria developed by the National Committee forClinical Laboratory Standards (NCCLS), as follows: susceptible strainshave MICs of ≦0.06 μg/ml, intermediate resistance is defined as an MICin the range 0.12 to 1.0 μg/ml whilst penicillin resistance is definedas an MIC of ≧2 μg/ml. Furthermore, it is found that some 10% ofpneumococci now have an amoxicillin MIC of 2 μg/ml.

There is consequently a need to provide new formulations ofamoxicillin/clavulanate that combine the known safety profile and broadspectrum with improved activity against DRSP, including PRSP, withhigher MICs in empiric treatment of respiratory infections where Spneumoniae, H influenzae and M catarrhalis are likely pathogens.

For β-lactams, including amoxicillin, it is recognised that the timeabove minimum inhibitory concentration (T>MIC) is the pharmacodynamicparameter most closely related to efficacy. For a variety of β-lactams,a bacteriological cure rate of 85 to 100% is achieved when serumconcentrations exceed the MIC for more than about 40% of the dosinginterval (Craig and Andes, Ped Inf Dis J, 1996, 15, 255-259). For a 12hour dosing interval, this is about 4.8 hours.

A further parameter which may be of importance is the ratio of themaximum plasma concentration (Cmax) to the MIC value, as this may berelated to the potential to select for resistance. Too low a ratio mayencourage the development of resistant strains. Preferably, the plasmaC_(max) value is well above the MIC value, for instance, at least twotimes, more preferably at least three times, most preferably at leastfour times, the MIC value.

In a clinical study using the existing Augmentin 875/125 mg tablet, itwas found that, when dosed at 12 hour intervals, the time above MIC wasabout 40% for an MIC of 2 μg/ml but only about 30% for an MIC of 4μg/ml. The existing Augmentin 875/125 mg tablet has a C_(max) value of11.6±2.8 μg/ml (Physicians Desk Reference, Medical Economics Co, 52edition, 1998, 2802).

Based on the foregoing considerations, there is a continuing need toprovide new dosage regimens for amoxicillin/clavulanate giving optimisedpharmacokinetic profiles for amoxicillin whilst not compromising thebioavailability of clavulanate, so that therapy is maximised,particularly against more resistant bacteria whilst the (further)development of resistance is minimised. It has now been found that suchcan be achieved using higher dosages of amoxicillin than previouslycontemplated.

Accordingly, in a first aspect, the present invention provides for amethod of treating bacterial infections in humans which comprises orallyadministering thereto a therapeutically effective amount of amoxicillinand potassium clavulanate such that the amount of amoxicillin is in therange 1900 to 2600 mg, preferably 1950 to 2550 mg, and the amount ofpotassium clavulanate is such that the weight ratio of amoxicillin toclavulanate is from 2:1 to 20:1, preferably 7:1 to 20:1, more preferably14:1 to 20:1, at intervals of about 12 hours (hereinafter “h”).

Preferably, the dosage regimen provides a mean plasma concentration ofamoxicillin of 4 μg/mL for at least 4.4 h, preferably at least 4.6 h,more preferably at least 4.8 h, most preferably for about 6 h or longer.

More preferably, the dosage regimen provides a mean plasma concentrationof amoxicillin of 8 μg/ml for at least 4.4 h, more preferably at least4.6 h, most preferably at least 4.8 h.

Preferably, the dosage regimen provides a mean maximum plasmaconcentration (C_(max)) of amoxicillin which is at least 8 μg/mL,preferably at least 12 μg/mL, yet more preferably at least 14 μg/mL,most preferably at least 16 μg/mL.

Preferably, the mean plasma concentration of amoxicillin and the meanmaximum plasma concentration of amoxicillin are measured after oraladministration of a formulation comprising amoxicillin at the start of alight meal.

In a further aspect, the present invention provides for a method oftreating bacterial infections in humans which comprises administeringthereto a therapeutically effective amount of amoxicillin and potassiumclavulanate such that the amount of amoxicillin is in the range 1400 to1900 mg, preferably 1500 to 1900 mg, and the amount of potassiumclavulanate is such that the weight ratio of amoxicillin to clavulanateis from 2:1 to 14:1, preferably 7:1 to 14:1, more preferably 12:1 to14:1, at intervals of about 12 h, such that the dosage regimen providesa mean plasma concentration of amoxicillin of 4 μg/mL for at least 4.4h, preferably at least 4.6 h, more preferably at least 4.8 h, mostpreferably for about 6 h or longer; more preferably, a mean plasmaconcentration of amoxicillin of 8 μg/ml for at least 4.4 h, morepreferably at least 4.6 h, most preferably at least 4.8 h, and a meanmaximum plasma concentration (C_(max)) of amoxicillin which is at least8 μg/mL, preferably at least 12 μg/mL, yet more preferably at least 14μg/mL, most preferably at least 16 μg/mL.

Bacterial infections amenable to the present invention includeinfections caused by the organisms S pneumoniae (including DrugResistant S pneumoniae (DRSP), for instance Penicillin Resistant Spneumoniae (PRSP)), and/or the β-lactamase producing respiratorypathogens, most notably H influenzae and M catarrhalis, such asrespiratory tract infections, including community acquired pneumoniae(CAP), acute exacerbations of chronic bronchitis (AECB) and acutebacterial sinusitis (ABS), where the higher break points achievablethrough the improved pharmacokinetic profile will be especiallyadvantageous compared to existing antibacterial agents. Most outpatientrespiratory infections are caused by either S pneumoniae and/or theβ-lactamase producing bacteria and are treated empirically so there is acontinuing need for a method of treatment, such as the presentinvention, that provides a spectrum of activity that covers all suchpathogens. The duration of therapy will generally between 7 and 14 days,typically 7 days for indications such as acute exacerbations of chronicbronchitis but 10 days for acute bacterial sinusitis. Typically, thedosages regimens are designed for adult patients, rather than paediatricpatients.

The term “amoxicillin” is used generically to refer to amoxicillin or analkaline salt thereof, in particular amoxicillin trihydrate and(crystallised) sodium amoxicillin, without distinction and unlessotherwise indicated.

Unless otherwise indicated, weights of amoxicillin and (potassium)clavulanate refer to the equivalent weights of the corresponding freeacids. In addition, it will be appreciated that in practice, weights ofamoxicillin and clavulanate to be incorporated into a formulation willbe further adjusted, in accord with conventional practice, to takeaccount of the potency of the amoxicillin and clavulanate.

In a first embodiment, a dosage of amoxicillin of from 1900 to 2600 mgand a corresponding amount of potassium clavulanate may delivered froman immediate release formulation. Accordingly, in a further aspect, thepresent invention provides for method of treating bacterial infectionsin humans which comprises administering thereto a therapeuticallyeffective amount of amoxicillin and potassium clavulanate such that theamount of amoxicillin is in the range 1900 to 2600, preferably 1950 to2550 mg, and the amount of potassium clavulanate is such that the weightratio of amoxicillin to clavulanate is from 2:1 to 20:1, preferably 7:1to 20:1, more preferably 14:1 to 20:1, at intervals of about 12 h,wherein the dosage is delivered from an immediate formulation.

As used herein, the term “immediate release” refers to the release ofthe majority of the active material content within a relatively shorttime, for example within 1 hour, preferably within 30 minutes, afteroral ingestion. Examples of such immediate release formulations includeconventional swallow tablets, dispersible tablets, chewable tablets,single dose sachets and capsules.

Representative dosages include 2000/125, 2250/125 and 2500/125 mg ofamoxicillin and potassium clavulanate, respectively. A preferred dosageis 2000/125 mg of amoxicillin and potassium clavulanate.

The dosage in an immediate release formulation may be provided as asingle tablet, for instance a dispersible tablet, a chewable tabletwhich may also be, effervescent and/or dispersible, a single dosecapsule or a single dosage sachet, comprising, for instance, 2000, 2250or 2500 mg amoxicillin and 125 mg potassium clavulanate. Alternatively,the dosage may be made up of a number of smaller tablets or capsules,for instance, 2, 3 or 4, some of which may be the same and some of whichmay comprise amoxicillin only and no potassium clavulanate.Representative such smaller tablets include swallow tablets, dispersibletablets and chewable tablets which may also be effervescent and/ordispersible. Thus, for instance, a dosage of 2000 mg amoxicillin and 125mg potassium clavulanate may be provided by a combination of threetablets each comprising 500 mg amoxicillin and one tablet comprising 500mg amoxicillin and 125 mg potassium clavulanate. Alternatively, such adosage may be provided by two tablets each comprising 1000/62.5 mgamoxicillin/potassium clavulanate. In addition, a dosage of 2250 mgamoxicillin and 125 mg potassium clavulanate may be provided by acombination of four tablets comprising 500 mg amoxicillin and one tabletcomprising 250 mg amoxicillin and 125 mg potassium clavulanate or twotablets comprising 875 mg amoxicillin and one tablet comprising 500 mgamoxicillin and 125 mg potassium clavulanate. Furthermore, a dosage of2500 mg amoxicillin and 125 mg potassium clavulanate may be provided bya combination of four tablet comprising 500 mg amoxicillin and onetablet comprising 500 mg amoxicillin and 125 mg potassium clavulanate.Tablets comprising 500 and 875 mg amoxicillin and 250/125, 500/125 and875/125 mg amoxicillin/potassium clavulanate are already commerciallyavailable.

It will be appreciated that immediate release tablets comprising1000/62.5 mg are novel. Accordingly, in a further aspect, the presentinvention provides for an immediate release pharmaceutical tabletformulation comprising 1000 mg±5% amoxicillin and 62.5 mg±5% potassiumclavulanate, in a nominal ratio of about 16:1, in combination withpharmaceutically acceptable excipients or carriers. Immediate releasetablets comprising 1000/62.5 mg can be readily prepared by adaptingcompositions previously described for 875/125 and 1000/125 mg tablets(see for instance, WO 95/28927 and WO 98/35672, SmithKline Beecham).

It will also be appreciated that immediate release single dosage sachetscomprising 2000/125 mg, 2250/125 mg or 2500/125 mg, or the correspondinghalf quantities thereof, are novel. Accordingly, in a further aspect,the present invention provides for an immediate release pharmaceuticalformulation in the form of a single dose sachet comprising 2000, 2250 or2500 mg±5% amoxicillin and 125 mg±5% potassium clavulanate, in a nominalratio of about 16:1, 18:1 or 20:1, respectively, or the correspondinghalf quantities thereof, in combination with pharmaceutically acceptableexcipients or carriers. Such sachets can be readily prepared by adaptingcompositions previously described for 875/125 and 1000/125 mg sachets(see for instance, WO 92/19277 and WO 98/35672, SmithKline Beecham).

It will be further appreciated that immediate release chewable tabletscomprising 2000, 2250 or 2500/125 mg are novel. Accordingly, in afurther aspect, the present invention provides for an immediate releasepharmaceutical formulation in the form of a chewable, optionallyeffervescent, tablet comprising 2000, 2250, or 2500 mg amoxicillin and125 mg±5% potassium clavulanate, in a nominal ratio of about 16:1, 18:1or 20:1, respectively, or the corresponding half quantities thereof, incombination with a chewable base and, if effervescent, an effervescentcouple, and other pharmaceutically acceptable excipients or carriers.Such chewable tablets can be readily prepared by adapting compositionspreviously described for chewable tablets comprising amoxicillin andpotassium clavulanate (see for instance, EP-A-0 396 335, Beecham Groupand WO 98/35672, SmithKline Beecham).

In a second embodiment, a dosage of amoxicillin of from 1900 to 2600 mgand a corresponding amount of potassium clavulanate may be deliveredfrom a modified release formulation. Accordingly, in a further aspect,the present invention provides for method of treating bacterialinfections in humans which comprises administering thereto atherapeutically effective amount of amoxicillin and potassiumclavulanate such that the amount of amoxicillin is in the range 1900 to2600 mg, preferably 1950 to 2550 mg, and potassium clavulanate ispresent in a pro rata amount such that the weight ratio of amoxicillinto potassium clavulanate is from 2:1 to 20:1, preferably 7:1 to 20:1,more preferably 14:1 to 20:1, at intervals of about 12 h, in which thedosage is delivered from a modified release formulation.

In a third embodiment, a dosage of amoxicillin of from 1400 to 1900 mgand a corresponding amount of clavulanate may be delivered from themodified release formulation. Accordingly, in a further aspect, thepresent invention provides for method of treating bacterial infectionsin humans which comprises administering thereto a therapeuticallyeffective amount of amoxicillin and potassium clavulanate such that theamount of amoxicillin is in the range 1400 to 1900 mg, preferably 1500to 1900 mg, and potassium clavulanate is present in a pro rata amountsuch that the weight ratio of amoxicillin to clavulanate is from 2:1 to14:1, preferably 7:1 to 14:1, more preferably 12:1 to 14:1, at intervalsof about 12 h, in which the dosage is delivered from a modified releaseformulation.

As used herein, the term “modified release” refers to a release of drugsubstance from a pharmaceutical formulation which is at a slower ratethan from an immediate release formulation such as a conventionalswallow tablet or capsule and may include an immediate release phase anda slow release phase. Modified release formulations are well known inthe art, see for instance Remington: The Science and Practice ofPharmacy, Nineteenth Edn, 1995, Mack Publishing Co, Pennsylvania, USA.

Preferably, the modified release formulations of the present inventionare formulated such that the release of amoxicillin is effectedpredominantly through the stomach and small intestine, so thatabsorption through the specific amoxicillin absorption site in the smallintestine is maximised. Preferably, the amoxicillin release profile ismade up of a contribution from an immediate release component which isthen complemented and extended by an on-going contribution from a slowrelease component. Preferably, potassium clavulanate is releasedsubstantially immediately from the formulation, when the formulationreaches the stomach and is absorbed therefrom, thereby minimising therisk of degradation from prolonged exposure to the stomach. Suchformulations are preferably formulated such that the release ofamoxicillin and potassium clavulanate occurs predominantly within 3hours of ingestion of the formulation.

Typically, a dosage will provide 125 mg of potassium clavulanate, theamount approved in existing regimens where a lesser amount ofamoxicillin is administered.

Representative modified release dosages include 1500/125, 1750/125 and2000/125 mg of amoxicillin and potassium clavulanate, respectively. Apreferred dosage is 2000/125 mg of amoxicillin and potassiumclavulanate.

The dosage in a modified release formulation may conveniently beprovided as a number of swallow tablets or capsules, for instance two,three or four, some of which may be the same and some of which maycomprise amoxicillin only and no potassium clavulanate. Thus, forinstance, a dosage of 2000 mg amoxicillin and 125 mg potassiumclavulanate may be provided by two tablets each comprising 1000/62.5 mgamoxicillin/potassium clavulanate, one tablet comprising 1000 mg ofamoxicillin and one tablet comprising 1000/125 mg amoxicillin/potassiumclavulanate, two tablets each comprising 500 mg amoxicillin and onetablet comprising 1000/125 mg amoxicillin/potassium clavulanate or fourtablets each comprising tablet 500/32.25 mg amoxicillin/potassiumclavulanate. In addition, a dosage of 1750 mg amoxicillin and 125 mgpotassium clavulanate may be provided by two tablets each comprising875/62.5 mg amoxicillin/potassium clavulanate or one tablet comprising875 mg of amoxicillin and one tablet comprising 875/125 mgamoxicillin/potassium clavulanate. A preferred tablet comprises1000/62.5 mg amoxicillin/potassium clavulanate.

The dosage in an modified release formulation may be may also providedas a single tablet. Because of the quantities of drug substance beingused, this would preferably be other than a swallow tablet, for instancea dispersible tablet or a chewable tablet which may also be effervescentand/or dispersible or a dispersible tablet. A single unit dosage mayalso be conveniently provided as a single dosage sachet. It will beappreciated that the dosage may also be provided as a number of smallernon-swallow tablets or sachets, for instance 2×1000/62.5 mg or 4×500/32.25 mg amoxicillin/potassium clavulanate.

Preferably, in the modified release formulation, all the potassiumclavulanate is provided in an immediate release phase whilst amoxicillinis provided in both an immediate release and a slow release phase.

Accordingly, in a further aspect, the present invention provides for amodified release pharmaceutical formulation comprising amoxicillin andpotassium clavulanate in the ratio from 2:1 to 20:1, preferably 7:1 to20:1, more preferably 12:1 to 20:1, most preferably 14:1 to 16:1 inwhich all of the potassium clavulanate and a first part of amoxicillinare formulated with pharmaceutically acceptable excipients which allowfor immediate release of the potassium clavulanate and the first part ofamoxicillin, to form an immediate release phase, and further comprisinga second part of amoxicillin formulated with pharmaceutically acceptableexcipients which allow for slow release of the second part ofamoxicillin, to form a slow release phase.

As used herein, the term “slow release” refers to the gradual butcontinuous or sustained release over a relatively extended period of theactive material content (in this case amoxicillin) after oral ingestionand which starts when the formulation reaches the stomach and starts todisintegrate/dissolve. The release will continue over a period of timeand may continue through until and after the formulation reaches theintestine. This can be contrasted with the term “delayed release” inwhich release of the active does not start immediately the formulationreaches the stomach but is delayed for a period of time, for instanceuntil when the formulation reaches the intestine when the increasing pHis used to trigger release of the active from the formulation.

Preferably, the modified release formulation has an in vitro dissolutionprofile in which 45 to 65%, preferably 45 to 55% of the amoxicillincontent is dissolved within 30 min; further in which 50 to 75%,preferably 55 to 65% of the amoxicillin content is dissolved within 60min; further in which 55 to 85%, preferably 60 to 70% of the amoxicillincontent is dissolved within 120 min; further in which 70 to 95%,preferably 75 to 85% of the amoxicillin content is dissolved within 180min; and further in which 70 to 100%, preferably 75 to 100% of theamoxicillin content is dissolved within 240 min. In comparison, aconventional, immediate release amoxicillin tablet dissolves essentiallycompletely within 30 minutes. The dissolution profile may be measured ina standard dissolution assay, for instance <711 > Dissolution Test,Apparatus 2, provided in USP 23, 1995, at 37.0±0.5° C., using deionisedwater (900 mL) and a paddle speed of 75 rpm.

Preferably, the modified release formulation has a biphasic profile invivo with respect to amoxicillin, that is an initial burst from theimmediate release phase to provide an acceptable C_(max) value,supplemented by a further contribution from the slow release phase, toextend the T>MIC parameter to an acceptable value.

Preferably, the modified formulation provides an “Area Under the Curve”(AUC) value which is substantially similar to, for instance at least80%, preferably at least 90%, more preferably about 100%, of that of thecorresponding dosage of amoxicillin taken as a conventional (immediaterelease) formulation, over the same dosage period, thereby maximisingthe absorption of the amoxicillin component from the slow releasecomponent.

The pharmcokinetic profile for a dosage of the present invention may bereadily determined from a single dosage bioavailability study in humanvolunteers. Plasma concentrations of amoxicillin may then be readilydetermined in blood samples taken from patients according to procedureswell known and documented in the art.

Representative modified release formulations include a tablet, includingswallow tablets, dispersible tablets, chewable tablets which may also beeffervescent and/or dispersible and, a capsule, granules or a sachet,typically a swallow tablet.

Representative modified release formulations having an immediate and aslow release phase provide a unit dosage in the range 700 to 1300 mg,preferably, 950 to 1300 mg, amoxicillin, for instance unit dosages of1000, 875 and 750/62.5 mg amoxicillin/clavulanate. Alternatively, andwhere the physical size of the dosage form is not a problem, the unitdosage may provide the whole dosage, for instance a single dosagesachet, chewable tablet or dispersible tablet may comprise 1400 to 2600mg, preferably, 1900 to 2600 mg, amoxicillin, for instance unit dosagesof 2000, 1750 and 1500/125 mg amoxicillin/clavulanate. It will beappreciated that such 1000, 875 and 750/62.5 mg formulations are novel.

Accordingly, in a further aspect, the present invention provides for apharmaceutical formulation having an immediate release phase and a slowrelease phase and comprising:

(a) a unit dosage in the range 700 to 1300 mg, preferably, 950 to 1300mg, amoxicillin, and a corresponding amount of potassium clavulanate, ina nominal ratio of about 16:1, 14;1 or 12:1, for instance unit dosagesof 1000, 875 or 750 mg±5% amoxicillin and 62.5 mg±5% potassiumclavulanate, respectively, or

(b) a unit dosage in the range 1400 to 2600 mg, preferably, 1900 to 2600mg, amoxicillin, and a corresponding amount of potassium clavulanate, ina nominal ratio of about 16:1, 14;1 or 12:1, for instance unit dosagesof 2000, 1750 or 1500 mg±5% amoxicillin and 62.5 mg±5% potassiumclavulanate, respectively, in combination with pharmaceuticallyacceptable excipients or carriers.

Preferably, the ratio of amoxicillin in the immediate and slow releasephases is from 3:1 to 1:3, more preferably, from 2:1 to 2:3, yet morepreferably 3:2 to 1:1. Representative ratios include about 2:1, 9:7 or1:1. It is found useful to employ an excess of amoxicillin in theimmediate release phase, to ensure an adequate C_(max) value.

In the modified release formulations of the present invention, theportion of amoxicillin which is released immediately may be provided asamoxicillin trihydrate or an alkaline salt thereof, for instancepotassium or sodium amoxicillin, preferably, (crystallised) sodiumamoxicillin or a mixture thereof, preferably amoxicillin trihydrate;whilst the portion of amoxicillin which is released slowly is providedas amoxicillin trihydrate or an alkaline salt thereof, for instancepotassium or (crystallised) sodium amoxicillin or a mixture thereof,preferably (crystallised) sodium amoxicillin.

Preferably, the modified release formulation is a tablet. In a preferredmodified release tablet comprising 1000 mg amoxicillin and 62.5 mgpotassium clavulanate, the immediate release phase comprises about 563mg±5% amoxicillin trihydrate and about 62.5 mg±5% of potassiumclavulanate and the slow release phase about 438 mg±5% of amoxicillin,preferably as (crystallised) sodium amoxicillin.

In a representative modified release tablet of the present invention,the immediate release phase comprises about 438 mg amoxicillin,preferably amoxicillin trihydrate and about 62.5 mg of potassiumclavulanate and the slow release phase about 438 mg of amoxicillin,preferably (crystallised) sodium amoxicillin, providing overall an875/62.5 mg (14:1) tablet.

In a further representative tablet of the present invention, theimmediate release phase comprises about 500 mg amoxicillin and about62.5 mg of potassium clavulanate and the slow release phase about 250 mgof amoxicillin, preferably (crystallised) sodium amoxicillin, providingoverall a 750/62.5 mg (12:1) tablet.

It will be appreciated that the use of a mixture of amoxicillintrihydrate and sodium amoxicillin is more generally applicable to otherpharmaceutical formulations comprising amoxicillin and potassiumclavulanate.

Accordingly, in a further aspect, the present invention provides for apharmaceutical formulation comprising amoxicillin and potassiumclavulanate in a ratio of from 1:1 to 30:1, preferably 2:1 to 20:1, morepreferably 12:1 to 20:1, yet more preferably 14:1 to 16:1, in whichamoxicillin is provided as a mixture of amoxicillin trihydrate andsodium amoxicillin in a ratio of from 3:1 to 1:3, more preferably from2:1 to 2:3, yet more preferably 3:2 to 1:1. Preferably, sodiumamoxicillin is crystallised sodium amoxicillin. Representativeformulation types include tablets, including immediate release andmodified release tablets as herein described, as well as other soliddosage forms such as capsules, single dosage sachets and granules.Representative tablets include those comprising 1000, 875, 500 and 250mg amoxicillin and a corresponding weight of potassium clavulanate.Representative ratios include 4:1, 7:1, 8:1, 14:1, and 16:1 (amoxicillin:clavulanate). Preferably, in modified release formulations of thepresent invention, the amoxicillin in the immediate release phaseconsists essentially of amoxicillin trihydrate and the amoxicillin ofthe slow release phase consists essentially of sodium amoxicillin.

For a tablet formulation, the immediate and slow release phases may beprovided in a number of different formats.

In a preferred aspect, the immediate and slow release phases areprovided as separate layers of a layered tablet.

Accordingly, in a further aspect, the present invention provides for alayered tablet formulation comprising potassium clavulanate andamoxicillin in an immediate release layer phase and amoxicillin in aslow release layer. The layered tablet may have two layers, or twolayers plus one or more barrier layer, as well as a coating layer. Asused herein, the term “bilayer” tablet refers to a tablet consisting ofan immediate release and a slow release layer, optionally with a coatinglayer.

An immediate release layer may be, for example, a layer whichdisintegrates immediately or rapidly and has a composition similar tothat of known tablets which disintegrate immediately or rapidly. Forexample, the layer may comprise, in addition to the active materialcontent, excipients including diluents such as microcrystallinecellulose; disintegrants such as cross-linked polyvinylpyrrolidone(CLPVP), sodium starch glycollate; compression aids such as colloidalsilicon dioxide and microcrystalline cellulose; and lubricants such asmagnesium stearate. Such an immediate release layer may comprise around60 to 85% (all percentages given herein are on a weight percentage basisunless otherwise stated), preferably 70 to 85%, of active materialcontent, around 10 to 30%, preferably 10 to 20% of fillers/compressionaids, and conventional amounts of disintegrants and lubricants,typically about 0.5 to 3%, etc.

An alternative type of immediate release layer may be a swellable layerhaving a composition which incorporates polymeric materials which swellimmediately and extensively in contact with water or aqueous media, toform a water permeable but relatively large swollen mass. Activematerial content may be immediately leached out of this mass.

Slow release layers have a composition which comprises amoxicillintogether with a release retarding excipient which allows for slowrelease of amoxicillin. Suitable release retarding excipients include pHsensitive polymers, for instance polymers based upon methacrylic acidcopolymers such as the Eudragit (trade mark) polymers, for exampleEudragit L (trade mark) which may be used either alone or with aplasticiser; release-retarding polymers which have a high degree ofswelling in contact with water or aqueous media such as the stomachcontents; polymeric materials which form a gel on contact with water oraqueous media; and polymeric materials which have both swelling andgelling characteristics in contact with water or aqueous media.

Release retarding polymers which have a high degree of swelling include,inter alia, cross-linked sodium carboxymethylcellulose, cross-linkedhydroxypropylcellulose, high-molecular weighthydroxypropylmethylcellulose, carboxymethylamide, potassiummethacrylatedivinylbenzene co-polymer, polymethylmethacrylate,cross-linked polyvinylpyrrolidone, high-molecular weightpolyvinylalcohols etc.

Release retarding gellable polymers include methylcellulose,carboxymethylcellulose, low-molecular weighthydroxypropylmethylcellulose, low-molecular weight polyvinylalcohols,polyoxyethyleneglycols, non-cross linked polyvinylpyrrolidone, xanthangum etc.

Release retarding polymers simultaneously possessing swelling andgelling properties include medium-viscosity hydroxypropylmethylcelluloseand medium-viscosity polyvinylalcohols.

A preferred release-retarding polymer is xanthan gum, in particular afine mesh grade of xanthan gum, preferably pharmaceutical grade xanthangum, 200 mesh, for instance the product Xantural 75 (also known asKeltrol CR, Trade Mark, Monsanto, 800 N Lindbergh Blvd, St Louis, Mo.63167, USA). Xanthan gum is a polysaccharide which upon hydration formsa viscous gel layer around the tablet through which the active has todiffuse. It has been shown that the smaller the particle size, theslower the release rate. In addition, the rate of release of drugsubstance is dependent upon the amount of xanthan gum used and can beadjusted to give the desired profile. Controlled release formulationscomprising from 7.5 to 25% xanthan gum are described in EP 0 234 670-A(Boots Co plc). The preferred embodiment is a tablet comprisingibuprofen as the drug substance and 15-20% xanthan gum, which is takenonce daily.

Examples of other polymers which may be used include Methocel K4M (TradeMark), Methocel E5 (Trade Mark), Methocel E5(Trade Mark), Methocel E4M(Trade Mark), Methocel K15M (Trade Mark) and Methocel K100M (TradeMark). An example of a suitable polymer mixture is a mixture of MethocelE5 and K4M, for example 1:1, w:w.

Other known release-retarding polymers which may be incorporated includehydrocolloids such as natural or synthetic gums, cellulose derivativesother than those listed above, carbohydrate-based substances such asacacia, gum tragacanth, locust bean gum, guar gum, agar, pectin,carageenin, soluble and insoluble alginates, carboxypolymethylene,casein, zein, and the like, and proteinaceous substances such asgelatin.

Such a slow release layer may contain polymers which immediately swellin contact with water or aqueous media so that they form a relativelylarge swollen mass which is not immediately discharged from the stomachinto the intestine.

The slow release layer may also include diluents such as lactose;compression aids such as microcrystalline cellulose; and lubricants suchas magnesium stearate. The slow release layer may further comprisedisintegrants, such as cross-linked polyvinylpyrrolidone (CLPVP) andsodium starch glycollate; binders such as povidone(polyvinylpyrrolidone); desiccants, such as silicon dioxide; and solubleexcipients such as mannitol or other soluble sugars. Typically, the slowrelease layer comprises from about 60 to 80% by weight of amoxicillin;from 10 to 20% by weight of diluent/compression aid and from 1 to 2.5%by weight of lubricant.

When xanthan gum is used as release-retarding polymer, the layercontains from 60 to 80% of amoxicillin, 4 to 25%, preferably 4 to 15%,more preferably 5 to 15%, typically about 6 to 10%, of xanthan gum, from10 to 30%, preferably 10 to 20% of fillers/compression aids, andconventional quantities of lubricants, all % being by weight of thelayer. In a preferred embodiment, the slow release layer comprises from70 to 80% of amoxicillin, from 4 to 10%, of xanthan gum, from 10 to 20%of microcrystalline cellulose, and from 1 to 2.5% of magnesium stearate,all % being by weight of the layer.

When release-retarding polymers other than xanthan gum are used, theslow release layer may contain around 30 to 70%, preferably from 40 to60%, of amoxicillin, from 15 to 45% of release-retarding polymer, from 0to 30% of fillers/compression aids, conventional quantities oflubricants, and from 5 to 20% of soluble excipients, all % being byweight of the layer.

It has also been surprisingly found that when the amoxicillin in theslow release layer is in the form of a soluble salt thereof, such assodium amoxicillin, then the release thereof may be retarded by theinclusion of an organic acid.

Accordingly, in a further aspect, the present invention provides for theuse of a pharmaceutically acceptable organic acid as a release retardingexcipient in a formulation comprising a pharmaceutically acceptablesoluble salt of amoxicillin, for instance sodium or potassiumamoxicillin, preferably sodium amoxicillin.

It will be appreciated that the use of an organic acid as a releaseretarding excipient is more generally applicable beyond the particularformulations hereinbefore described.

Accordingly, the present invention further provides for a pharmaceuticalformulation comprising a pharmaceutically acceptable soluble salt ofamoxicillin, for instance sodium amoxicillin, in a slow release phasewhich further comprises a release retarding excipient which is apharmaceutically acceptable organic acid present in a molar ratio offrom 100:1 to 1:10, preferably 50:1 to 1:5, more preferably 20:1 to 1:2(amoxicillin to organic acid).

It is believed that intimate contact between the organic acid and thesalt of amoxicillin in the pharmaceutical formulation, for instance as aconsequence of compacted granule formation or direct compression in atablet, causes some form of interaction which modifies the release ofthe amoxicillin component from the formulation.

Soluble pharmaceutically acceptable salts of amoxicillin include alkalimetal salts such as sodium and potassium; alkaline earth metal saltssuch as magnesium and calcium, and acid salts such as amoxicillinhydrochloride. Preferably, the salt is sodium amoxicillin, morepreferably crystalline sodium amoxicillin.

As used herein, the term “pharmaceutically acceptable organic acid”refers to organic acids which are without pharmacological effect per se,have acceptable organoleptic properties, have acceptable density, do nothave an extreme pH and are preferably solid. Examples thereof includemono-carboxylic acids and poly-carboxylic acids having from 2 to 25,preferably from 2 to 10, carbon atoms; monocyclic and polycyclic arylacids such as benzoic acid; as well as monohydrogen, dihydrogen etcmetal salts of multi-valent acids. A single pharmaceutically acceptableorganic acid may be used, or two or more of such may be used incombination. Preferably, the organic acid is a C₍₂₋₁₀₎alkyl- oralkenyl-carboxylic acid having from one, two or three carboxylic acidgroups, and optionally with one or more hydroxy substituents or anadditional CO group in the carbon chain, for instance malonic acid,succinic acid, fumaric acid, maleic acid, adipic acid, lactic acid,levulinic acid, sorbic acid or a fruit acid such as tartaric acid, malicacid, ascorbic acid or citric acid, or an acidic salt thereof, morepreferably citric acid.

The organic acid may be used alone or in combination with a releaseretarding polymer as hereinbefore described. A preferred combinationcomprises citric acid and a release retarding gellable polymer, inparticular xanthan gum. In the presence of the organic acid, forinstance citric acid, xanthan gum may be used at a lower level then whenincluded on its own, for instance, from 0.5 to 8%, preferably 1 to 5%,typically about 2%, by weight of the slow release layer.

When an organic acid is used as a release-retarding excipient, the slowrelease layer contains from 60 to 80% of a soluble salt of amoxicillin,from 10 to 30%, preferably 10 to 20% of fillers/compression aids, andconventional quantities of lubricants, all % being by weight of thelayer. In a preferred embodiment, the slow release layer comprises from60 to 70% of a soluble salt of amoxicillin, from 10 to 20% ofmicrocrystalline cellulose, and from 1 to 2.5% of magnesium stearate,all % being by weight of the layer.

In a representative example, a layered tablet comprises in the slowrelease layer crystallised sodium amoxicillin and citric acid, in amolar ratio of about 50:1 to 1:2, preferably 20:1 to 1:2, morepreferably 2:1 to 1:1.2, yet more preferably about 1:1. In a preferredembodiment, the slow release layer comprises about 438 mg±5%crystallised sodium amoxicillin, about 78 mg±10% citric acid and about2% by weight of xanthan gum.

In a preferred layered tablet comprising 1000 mg amoxicillin and 62.5 mgpotassium clavulanate, the immediate release layer comprises about 563mg±5% amoxicillin, preferably amoxicillin trihydrate, and about 62.5mg±5% of potassium clavulanate and the slow release layer about 438mg±5% of amoxicillin, preferably crystallised sodium amoxicillin, about78 mg±10% citric acid and about 2% by weight of xanthan gum.

The tablet formulations of the invention may also include one or morebarrier layers, which may be located between the respective first andsecond layers, and/or on one or more of the outer surfaces of the firstand second layers, for example the end faces of the layers of asubstantially cylindrical tablet. Such barrier layers may, for example,be composed of polymers which are either substantially or completelyimpermeable to water or aqueous media, or are slowly erodable in wateror aqueous media or biological liquids and/or which swell in contactwith water or aqueous media. Suitably the barrier layer should be suchthat it retains these characteristics at least until complete orsubstantially complete transfer of the active material content to thesurrounding medium.

Suitable polymers for the barrier layer include acrylates,methacrylates, copolymers of acrylic acid, celluloses and derivativesthereof such as ethylcelluloses, cellulose acetate propionate,polyethylenes and polyvinyl alcohols etc. Barrier layers comprisingpolymers which swell in contact with water or aqueous media may swell tosuch an extent that the swollen layer forms a relatively large swollenmass, the size of which delays its immediate discharge from the stomachinto the intestine. The barrier layer may itself contain active materialcontent, for example the barrier layer may be a slow or delayed releaselayer. Barrier layers may typically have an individual thickness of 2 mmto 10 microns.

Suitable polymers for barrier layers which are relatively impermeable towater include the Methocel (trade mark) series of polymers mentionedabove, for example Methocel K100M, Methocel K15M, Methocel E5 andMethocel E50, used singly or combined, or optionally combined with anEthocel (trade mark) polymer. Such polymers may suitably be used incombination with a plasticiser such as hydrogenated castor oil. Thebarrier layer may also include conventional binders, fillers, lubricantsand compression acids etc such as Polyvidon K30 (trade mark), magnesiumstearate, and silicon dioxide, e.g. Syloid 244 (trade mark).

The tablet formulation of the invention may be wholly or partly coveredby a coating layer, which may be a protective layer to prevent ingressof moisture or damage to the tablet. The coating layer may itselfcontain active material content, and may, for example, be an immediaterelease layer, which immediately disintegrates in contact with water oraqueous media to release its active material content, for exampleamoxicillin and potassium clavulanate. Preferred coating materialscomprise hydroxypropylmethylcellulose and polyethylene glycol, withtitanium dioxide as an opacifying agent, for instance as described in WO95/28927 (SmithKline Beecham).

As well as active material content etc, the tablet of the invention mayalso include a pH modifying agent, such as a pH buffer, which may becontained in either the immediate-, or slow-release layers, or in acoating around all or part of the tablet. A suitable buffer is calciumhydrogen phosphate.

In a tablet without a barrier layer, the immediate release layercomprises from 50 to 60% and the slow release layer comprises from 40 to50% of the overall tablet weight. When a barrier layer is present, theimmediate release layer typically comprises from 40 to 50%, the slowrelease layer comprises from 35 to 45%, and the barrier layer comprisesfrom 5 to 20% of the overall tablet weight.

It is found that a satisfactory pharmacokinetic profile may be obtainedfrom a bilayered tablet of the present invention without the need toinclude a barrier layer. Accordingly, a bi-layer tablet is preferred.This also reduces the complexity of the manufacturing process.

It will be appreciated that 1000, 875 and 750/62.5 mg layered tabletshaving an immediate release layer and a slow release layer are novel.Accordingly, in a further aspect, the present invention provides for apharmaceutical layered tablet formulation comprising an immediaterelease layer and a slow release layer and comprising from 700 to 1250mg amoxicillin and a pro rata amount of potassium clavulanate,preferably 1000, 875 or 750 mg±5% amoxicillin and 62.5 mg±5% potassiumclavulanate, in a nominal ratio of about 16:1, 14:1 or 12:1,respectively, in combination with pharmaceutically acceptable excipientsor carriers. Preferably, the layered tablet is a bi-layered tablet.

Suitably the tablet formulations of the invention may be formed by knowncompression tabletting techniques, for example using a known multi-layertabletting press. Preferably, in a preliminary step, slugging or rollercompaction is used to form granulates. Lubricants and compression aids(if used) are then added, to form a compression blend for subsequentcompaction.

Preferred bilayer tablets of the present invention may be made by aprocess which comprises, as an early phase, the formation of slowrelease compacted granules, comprising the steps of milling sodiumamoxicillin, a portion of the diluent/compression aid such asmicrocrystalline cellulose (typically about 30%), a portion of thelubricant (typically about 70%) and a pharmaceutically acceptableorganic acid such as a fruit acid, for instance citric acid, and thenblending with a release retarding polymer such as xanthan gum, ifpresent, and a compression aid such as colloidal silicon dioxide,compacting the blend, for instance in a roller compactor or by slugging,and then milling, to form slow release granules. Preferably suchgranules have a size in the range 100 to 1000 microns. The incorporationof xanthan gum appears to also have an unexpected benefit onprocessibility.

Alternatively, slow release granules in which amoxicillin is present asamoxicillin trihydrate and the release modifying excipient is xanthangum may be prepared by a similar process. Such slow release compactedgranules may then be blended with other excipients such as the remainingmagnesium stearate and microcrystalline cellulose, to form a slowrelease compression blend.

In addition, amoxicillin trihydrate, potassium clavulanate (preferablyas as 1:1 blend with microcrystalline cellulose), microcrystallinecellulose (a portion of total used), are milled and blended with alubricant such as magnesium stearate (preferably about 50% f total), andthen compacted, for instance in a roller compactor or by slugging, andmilled to form immediate release compacted granules. These immediaterelease compacted granules may then be blended with other excipientssuch as the remaining magnesium stearate and microcrystalline cellulose(about 13%), a compression aid such as colloidal silica, and adisintegrant such as sodium starch glycollate, to form an immediaterelease compression blend.

The immediate release and slow release compression blends may then becompressed as separate layers on a bilayer tablet press, to form bilayertablets.

Such slow release granules are novel. Accordingly, in a further aspect,the present invention provides for compacted granules comprising asoluble salt of amoxicillin, for instance sodium amoxicillin, adiluent/compression aid, and an organic acid or a release retardingpolymer or a mixture thereof, as hereinbefore defined. In a yet furtheraspect, the present invention also provides for compacted granulescomprising amoxicillin trihydrate, a diluent/compression aid, and arelease retarding polymer, as hereinbefore defined Alternatively, a drydensification process may be used, e.g. briquetting. Typically theactive material content, pH modifiers, buffers, fillers and/or diluent,release retarding agents, disintegrants and binders, when used aremixed, then lubricants and compression aids are added. The completemixture may then be compressed under high pressure in the tablet press.A wet granulation process may be also be used, for instance withisopropanol as the solvent and Polyvidon K-30 (trade mark) as the wetgranulating aid.

A barrier layer, if present, may typically be made up by a wetgranulation technique, or by dry granulation techniques such as rollercompaction. Typically the barrier material, e.g. Methocel (trade mark)is suspended in a solvent such as ethanol containing a granulation acidsuch as Ethocel or Polyvidon K-30 (trade mark), followed by mixing,sieving and granulation. Typically a first layer may be formed, then abarrier layer deposited upon it, e.g. by compression, spraying orimmersion techniques, then the second layer may be formed so that thebarrier layer is sandwiched between the first and second layers.Additionally, or alternatively, the first and second layers may beformed and a barrier layer may then be formed, for instance bycompression, spraying or immersion, on one or more of the end faces ofthe tablet.

A process for the preparation of crystallised sodium amoxicillin isdescribed in EP-A-0 131 147 (Beecham Group plc).

Potassium clavulanate is known to be extremely water sensitive.Therefore tablet formulations which contain potassium clavulanate shouldbe made up in dry conditions, preferably at 30% relative humidity orless, and the ingredients of the formulation should be pre-dried whereappropriate. Tablet formulations of the invention should be stored incontainers which are sealed against the ingress of atmospheric moisture.

Tablet cores may then be coated with a coating layer which may beapplied form an aqueous or an organic solvent system, preferably anaqueous solvent system, to provide film coated tablets.

The invention also provides a method for the manufacture of a tabletformulation as described above comprising the steps of forming saidfirst and second layers, and any barrier layers and coating layer(s)which may be present.

In addition to the layered tablet approach hereinbefore described, othertypes of tablet may be used to provide an immediate release phase and aslow release phase, using the excipients hereinbefore described butproviding the phases in different formats. Thus, the slow release phasemay form the core of a tablet which is then surrounded by an outercasing forming the immediate release phase, optionally with anintermediate coating layer around the core and/or a final coating layeraround the outer casing (see WO 95/28148, SmithKline Beecham). The slowrelease phase may also be provided as granules which are dispersed in amatrix of amoxicillin and potassium clavulanate, the matrix forming theimmediate release phase (see WO 96/04908, SmithKline Beecham).

In a further variant, a monolith modified release tablet may be preparedfrom slow release compacted granules comprising amoxicillin, adiluent/compression aid such as microcrystalline cellulose, and apharmaceutically acceptable organic acid such as a fruit acid, forinstance citric acid (if amoxicillin is present as a soluble saltthereof), or a release retarding polymer such as xanthan gum or amixture thereof, preferably a release retarding polymer (as hereinbeforedescribed); and immediate release compacted granules comprisingamoxicillin and potassium clavulanate (as hereinbefore described) orimmediate release compacted granules comprising amoxicillin andpotassium clavulanate, for instance in a 2:1 ratio, and furtherimmediate release compacted granules comprising amoxicillin (asdescribed in WO 98/35672, SmithKline Beecham LaboratoiresPharmaceutiques), the granules being combined with extragranularexcipients to form tablets. Such granules may also be processed intoother pharmaceutical formulations, for instance single dosage sachets,capsules or chewable tablets comprising a unit dosage as hereinbeforedescribed.

Chewable tablets according to the present invention typically comprise achewable base formed from, for instance, mannitol, sorbitol, dextrose,fructose or lactose alone or in combination. A chewable tablet may alsocomprise further excipients, for instance, disintegrants, lubricants,sweetening agents, colouring and flavouring agents. Such furtherexcipients together will preferably comprise from 3 to 10%, morepreferably 4 to 8%, yet more preferably 4 to 7% by weight of the tablet.Disintegrants may be present in from 1 to 4%, preferably from 1 to 3%,more preferably from 1 to 2% by weight of the tablet. Representativedisintegrants include crospovidone, sodium starch glycollate, starchessuch as maize starch and rice strach, croscarmellose sodium andcellulose products such as microcrystalline cellulose, microfinecellulose, low substituted hydroxy propyl cellulose, either used singlyor in admixture. Preferably, the disintegrant is crospovidone.Lubricants may be present in from 0.25 to 2.0%, preferably from 0.5 to1.2% by weight of the tablet. Preferred lubricants include magnesiumstearate. Preferably, the sweetening agent is an artificial sweeteningagent such as sodium saccharin or aspartame, preferably aspartame, whichmay be present in from 0.5 to 1.5% by weight of the tablet. Preferably,a tablet of the present invention is substantially free of sugar(sucrose). Preferred flavouring agents include fruit flavours which maybe natural or synthetic, for instance peppermint, cherry and banana, ora mixture thereof.

Single dose sachets according to the present invention comprise, inaddition to the drug substance, excipients typically included in asachet formulation, such as a sweetener, for instance aspartame,flavourings, for instance fruit flavours, optionally a suspending agentsuch as xanthan gum, as well as silica gel, to act as a desiccant.

Capsules according to the present invention comprise, in addition to thedrug substance, excipients typically included in a capsule, for instancestarch, lactose, microcrystalline cellulose, magnesium stearate. It willbe appreciated that due to the hygroscopic nature of clavulanate, theuse of materials such as gelatin for forming the capsules should beavoided. Preferably, capsules are prepared from materials such as HPMCor a gelatin/PEG combination.

In a further embodiment, the slow release phase may be provided as aseparate component, for instance as a separate tablet, so that the unitdosage is provided as a combination of a conventional component in whichamoxicillin and potassium clavulanate are released immediately,optionally with a conventional amoxicillin formulation such as a tablet,and a further formulation, for instance a tablet, comprising amoxicillin(and no potassium clavulanate) from which amoxicillin is releasedslowly. The weight of potassium clavulanate and the combined weights ofamoxicillin in the conventional and slow release formulations willprovide the overall unit dosage. Thus, for instance a dosage of 2000/125mg may be provided by a combination of an existing 500/125 mgamoxicillin/potassium clavulanate tablet and a 500 mg amoxicillin tabletin combination with a slow release tablet comprising 1000 mg ofamoxicillin. Furthermore, a dosage of 1750/125 mg may be provided by anexisting 875/125 mg tablet (as described in WO 95/28927, SmithKlineBeecham) in combination with a slow release tablet comprising 875 mg ofamoxicillin. In addition, a dosage of 1500/125 mg may be provided by anexisting 500/125 mg tablet and an existing 500 mg tablet of amoxicillinin combination with a slow release tablet comprising 500 mg ofamoxicillin. Accordingly, in a further aspect, the present inventionprovides for a kit comprising a conventional (immediate release) tabletcomprising amoxicillin and potassium clavulanate, optionally with aconventional (immediate release) tablet comprising amoxicillin, and aslow release tablet comprising amoxicillin (and no potassiumclavulanate).

In a further aspect, the present invention provides for a pharmaceuticalformulation, preferably a tablet, comprising amoxicillin (as the soleactive ingredient) formulated with a release retarding excipient whichcauses a slow release of the amoxicillin from the formulation, andexcluding; tablets which comprise 750 mg or less of amoxicillin in whichthe amoxicillin is present essentially as amoxicillin trihydrate; ortablets comprising from 400 to 500 mg amoxicillin in which amoxicillinis present as a mixture comprising at least 70% amoxicillin trihydrateand up to 30% sodium amoxicillin in combination with hydroxypropylmethylcellulose as a release retarding excipient.

Such formulations may comprise from 100 to 1250 mg amoxicillin which maybe amoxicillin trihydrate or (crystallised) sodium amoxicillin or amixture thereof, for instance 500, 875 or 1000 mg amoxicillin. Suitableexcipients for slow release are those hereinbefore described for slowrelease layers. The formulation may comprise from 4 to 25%, preferablyfrom 4 to 15%, more preferably 4 to 10% of xanthan gum, or from 10 to25, preferably 15 to 20% of a hydroxypropyl-methylcellulose, forinstance Methocel K100LV or Methocel K4M. Alternatively, suchformulations may comprise citric acid, optionally with xanthan gum, ashereinbefore described.

The modified release formulations of the present invention are intendedfor use in a bid dosing regimen. It will be appreciated that whilst sucha bid dosing regimen is recognised to offer the advantage of greaterconvenience and therefore likely greater compliance, in some instances,it may be preferred to use administer the same total daily dosage but ina tid regimen, that is in equally divided doses every 8 hours, ratherthan every 12 hours. Accordingly, in a further aspect, the presentinvention provides for a method of treating bacterial infections inhumans which comprises orally administering thereto a therapeuticallyeffective amount of amoxicillin and potassium clavulanate such that theamount of amoxicillin is in the range 1250 to 1750 mg, preferably 1300to 1700 mg, and the amount of potassium clavulanate is such that theweight ratio of amoxicillin to clavulanate is from 2:1 to 20:1,preferably 7:1 to 20:1, more preferably 14:1 to 20:1, at intervals ofabout 8 h, in which the dosage is delivered from a modified releaseformulation.

Preferably, the dosage regimen provides a mean plasma concentration ofamoxicillin of 4 μg/mL for at least. 3.0 h, preferably at least 3.2 h,more preferably at least 3.6 h, most preferably for about 4 h or longer.

More preferably, the dosage regimen provides a mean plasma concentrationof amoxicillin of 8 μg/ml for at least 3.0 h, more preferably at least3.2 h, most preferably at least 3.6 h.

Preferably, the dosage regimen provides a mean maximum plasmaconcentration (Cmax) of amoxicillin which is at least 8 μg/mL,preferably at least 12 μg/mL, yet more preferably at least 14 μg/mL,most preferably at least 16 μg/mL.

A preferred dosage is in the range 1300 to 1700 mg amoxicillin and 125mg potassium clavulanate, more preferably 1400 to 1600 mg amoxicillinand 125 mg potassium clavulanate.

Such a dosage may be provided by one or two modified releasepharmaceutical formulations, in particular two bilayer or monolithswallow tablets each comprising half the dosage (for instance, 650 to850 mg amoxicillin, more preferably 700 to 800 mg amoxicillin, and 62.5mg potassium clavulanate) or a larger chewable tablet or single dosesachet comprising the entire unit dosage (for instance, 1300 to 1700 mgamoxicillin, more preferably 1400 to 1600 mg amoxicillin, and 125 mgpotassium clavulanate), by appropriate adjustment to the correspondingformulations hereinbefore described. A representative tablet comprises750 mg of amoxicllin and 62.5 mg of potassium clavulanate, having anominal ratio of amoxicllin :potassium clavulanate of 12:1. Such atablet may comprise from 300 to 450 mg of amoxicillin in the immediaterelease phase and from 300 to 450 mg of amoxicllin in the slow releasephase, to make a total of 750 mg amoxicillin. A further representativetablet comprises 675 mg of amoxicllin and 62.5 mg of potassiumclavulanate. Such a tablet may comprise from 250 to 400 mg ofamoxicillin in the immediate release phase and from 250 to 400 mg ofamoxicllin in the slow release phase, to make a total of 675 mgamoxicillin.

It will be further appreciated that the methods and formulationshereinbefore described for amoxicillin and clavulanate are alsoapplicable to amoxicillin alone, with no clavulanate, particularly fortreating infections where β-lactamase producing pathogens are notimplicated, for instance infections caused by the organism Streptococcuspyogenes, such acute bacterial tonsillitis and/or pharyngitis. Thepresent invention also all such uses and formulations of amoxicillin asthe sole agent.

Preferably, the unit dosage forms of the present invention are packagedin containers that inhibit the ingress of atmospheric moisture, forinstance blister packs, tightly closed bottles or desiccated pouch packsetc which are conventional in the art. Preferably, bottles also includea desiccating material, to preserve the clavulanate. Preferred bottlesinclude HDPE bottles. Preferred blister packs include cold-formedblister packs in which each blister may contain one tablet, or twotablets, where the unit dosage is two tablets, for instance 2×1000/62.5mg tablets, to improve patient compliance.

All publications and references, including but not limited to patentsand patent applications, cited in this specification are hereinincorporated by reference in their entirety as if each individualpublication or reference were specifically and individually indicated tobe incorporated by reference herein as being fully set forth. Any patentapplication to which this application claims priority is alsoincorporated by reference herein in its entirety in the manner describedabove for publications and references. The invention will now bedescribed by way of example.

EXAMPLES

The foregoing examples describe tablet formulations which comprisepotassium clavulanate. This is known to be extremely water sensitive.Therefore such tablet formulations should be made up in dry conditions,preferably at 30% relative humidity or less, and the ingredients of theformulation should be pre-dried where appropriate.

Example 1 1000/62.5 mg Modified Release Tablet

Ingredient mg/tablet % w/w Immediate Release Layer AmoxicillinTrihydrate (ERH <40%) 654.1* 40.88 Potassium Clavulanate 76.2# 4.76Microcrystalline Cellulose 136.4 8.52 Sodium Starch Glycollate 18.0 1.12Colloidal Silicon Dioxide 6.3 0.39 Magnesium Stearate 9.0 0.56 Total(Immediate Release Layer) 900.0 56.23 Slow Release Layer CrystallisedSodium Amoxicillin 480.8** 30.05 Microcrystalline Cellulose 113.2 7.08Xanthan Gum 14.0 0.87 Citric Acid 78.0 4.87 Colloidal Silicon Dioxide1.50 0.08 Magnesium Stearate 14.0 0.87 Total (Sustained Release Layer)700.0 43.74 Film coat Opadry YS-1-7700 - Composition:Hydroxypropylmethylcellulose 2910 6 cp 11.6 Hydroxypropylmethylcellulose2910 15 cp 3.9 Titanium dioxide 15.1 Polyethylene Glycol 3350 2.3Polyethylene Glycol 8000 2.3 Total weight of coated tablet 1635.2*Equivalent to 562.5 mg of amoxicillin based on an assay of 86.0%#Equivalent to 62.5 mg of clavulanic acid based on an assay of 82.0%**Equivalent to 437.5 mg amoxicillin based on an assay of 91.0%

Example 2

1000/62.5 mg modified release tablet The immediate release layer andfilm coat are as for the tablet of Example 1 Ingredient mg/tablet % w/wSlow Release Layer Crystallised Sodium Amoxicillin 480.8** 30.05Microcrystalline Cellulose 127.2 7.95 Citric Acid 78.0 4.87 ColloidalSilicon Dioxide 1.5 0.09 Magnesium Stearate 14.0 0.87 Total (SlowRelease Layer) 700.0 43.74 Total Weight of coated tablet 1635.2**Equivalent to 437.5 mg amoxicillin based on an assay of 91.0%Preparation of Modified Release Tablets

Modified release tablets were prepared according to the process flowdiagram shown in FIG. 2. In brief, immediate and modified release blendsare prepared which involve initial sieving and milling, as indicated,before roller compaction in a Chilsonater and further milling, sievingand blending. The two containers comprising amoxicillin trihydrate andthe two containers comprising sodium amoxicillin comprise about equalweights of amoxicillin trihydrate and sodium amoxicillin, respectively.

For the IR blend, the Chilsonator settings were: roll size, width=4inches, diam=10 inches; hydraulic pressure=900-1100 psi, airpressure=25-35 psi, roll speed=15-25 rpm, horizontal auger speed=15-30rpm, vertical auger speed=300-350 rpm.

For the SR blend, the Chilsonator settings were: roll size, width=4inches, diam=10 inches; hydraulic pressure=500-700 psi, airpressure=15-20 psi, roll speed=15-25 rpm, horizontal auger speed=30-35rpm, vertical auger speed=300-350 rpm.

The two blends were then compressed as separate layers in a bilayertablet press equipped with punches measuring 0.0406 inches by 0.8730inches and having a modified capsule shape. For the first (immediaterelease)layer, there was no pre-compression, and a main compression ofless than 10 KN. For the second layer, there was a pre-compression ofless than 20 KN, and a main compression of less than 60 KN. The tabletsthus produced had a total weight of 1600 mg±48 mg, a hardness in therange 8 to 18 SCU and a friability of less than 0.5%.

Finally, the tablet cores were coated with an aqueous film coating,using a 15% solids aqueous suspension, in a 60 inch coating pan whichcould accommodate up to 300 kg charge of tablets. The pan was equippedwith 4 spray guns and rotated at 3 to 5 rpm. The inlet air wasdehumidified with the temperature in the range 56 to 60° C. whilst theexhaust air humidity was in the range 4 to 12% and the temperature inthe range 43 to 50° C. The spray rate was 80 to 120 ml/min/spray gun.

Example 3 Slow Release Tablet (875 mg)

mg/ta

(a) Sodium Amoxicillin Tablet Crystallised Sodium Amoxicillin 91%* 961

73

Dried Microcrystalline Cellulose 273

21

Magnesium Stearate 1

1

Xanthan gum 200 mesh** 5

4

Total 1

(b) Sodium Amoxicillin Tablet with citric acid Crystallised SodiumAmoxicillin 91%* 961

66

Dried Microcrystalline Cellulose 288

19

Magnesium Stearate 14

1

Citric acid 10

Xanthan gum 200 mesh** 2

2

Total 1

(c) Amoxicillin Trihydrate Tablet Amoxicillin Trihydrate 86%* 101

78

Dried Microcrystalline Cellulose 21

16

Magnesium Stearate 1

1

Xanthan Gum, 200 mesh** 5

4

Total 1

*adjusted for the potency of the amoxicillin component and correspondingto 875 mg amoxicillin,**Xantural 75

Example 4 875/62.5 mg Modified Release Tablet

Slow Release Layer

This may be formed using half the quantities given above, for a slowrelease layer comprising about 438 mg amoxicillin. Immediate releaselayer - 1 Amoxicillin trihydrate 507 mg (equiv to amoxicillin free acid)(438)   Potassium clavulanate 71.8 (equivalent to clavulanic acid)(62.5) Microcrystalline cellulose (Avicel PH102) 125 Sodium starchglycollate (Explotab) 26 Magnesium stearate 6.5

The immediate release layer comprises nominally 438/62.5 mgamoxicillin/clavulanate. Immediate release layer - 2 Amoxicillintrihydrate 507 mg (equiv to amoxicillin free acid) (438)   Potassiumclavulanate 71.8 (equivalent to clavulanic acid) (62.5) Microcrystallinecellulose (Avicel PH102) 135 Sodium starch glycollate (Explotab) 34 Talc67 Magnesium stearate 25 Silica (Syloid) 17The immediate release layer comprises nominally 438/62.5 mgamoxicillin/clavulanate.Barrier Layers

Barrier layers and methods for their preparation are described in WO95/20946 (SmithKline Beecham) whose disclosure is incorporated herein byreference in its entirety.

Preparation of Tablets

The active ingredients, fillers and diluents (microcrystallinecellulose), release controlling agents (if present), disintegrants(crospovidone, sodium starch glycollate) etc are mixed. Lubricants(talc, Mg-stearate) and colloidal silicon dioxide (Syloid 244) areadded, and mixing is continued for another minute. The complete mixtureis slugged on a tablet press or roller compacted (briquetting step),followed by size reduction (Apex, Fitzmill, Frewitt) and passage throughan oscillatory sieve or particle size classifier (Kason, Sweco). If theflow properties are unsatisfactory, the briquetting step is repeated.Separate compressed blends are prepared for the immediate and slowrelease layers, and barrier layer, if present.

In some cases, where the bulk density is rather low, a densifying step(pre-tabletting and sieving as in the briquetting method) may berequired in order to achieve the nominal weight of a particular layer.

The blends are then compressed as separate layers on a layer tabletpress to form bilayered tablets. Tablets may then be coated with a whiteopaque coating, for instance the product Opadry, Opaspray (Colorcon).

Example 5

mg/tablet % Crystallised Sodium Amoxicillin¹ 824.2 51.51 AmoxicillinTrihydrate² 290.7 18.17 Clavulanate Potassium³ 76.2 4.76 DriedMicrocrystalline Cellulose 165.9 10.37 Magnesium Stearate 23.0 1.44Sodium Starch glycollate 80.0 5.00 Colloidal silicon dioxide 6.3 0.39Citric acid 133.7 8.36 Total 1600 100.0¹adjusted for potency of the amoxicillin component and corresponding to750 mg of amoxicillin²adjusted for potency of the amoxicillin component and corresponding to250 mg of amoxicillin³adjusted for potency of the clavulanate potassium component andcorresponding to 62.5 mg of clavulanate potassium

Two separate batches of granules, the first, immediate release granules,comprising amoxicillin and potassium clavulanate and the second, slowrelease granules, comprising sodium amoxicillin and citric acid, wereprepared by roller compaction, as described in Example 2, and thencombined with the remaining excipients, blended and formed into tabletsin a tablet press.

Example 6 1000 mg Monolith Tablet

A tablet similar to the tablet of Example 5 may be prepared in which theratio of amoxicillin trihydrate to sodium amoxicillin is adjusted from1:3 to 9:7 (563/438 mg)

Example 7 875 mg Slow Release Tablet

Ingredient mg/tablet % w/w Sodium Amoxicillin 961.5 73.96Microcrystalline Cellulose 218.5 16.81 Xanthan gum 97.5 7.50 ColloidalSilicon Dioxide 3.0 0.23 Magnesium Stearate 19.5 1.50 Total 1300.0100.00**Equivalent to 875 mg amoxicillin based on an assay of 91.0%

Slow release tablets were prepared from slow release granules using theprocess described above in Example 1. The granules were then blendedwith the remaining ingredients and compressed in a tablet press intotablets.

Example 8 875 mg Slow Release Tablet

A tablet similar to the tablet of Example 7 was prepared in which thelevel of xanthan gum was increased to 195 mg (15%), with a correspondingreduction in the weight of microcrystalline cellulose.

Example 9 875 mg Slow Release Tablet

A tablet similar to the tablet of Example 7 was prepared in which thesodium amoxicillin was replaced by an equivalent amount of amoxicillintrihydrate (1017.4 mg, 78.26%) with a corresponding reduction in theweight of microcrystalline cellulose

Example 10 Dissolution Testing Methods

The release of amoxicillin and clavulanate from tablets into staticmedia was measured using the <711 > Dissolution Test, Apparatus 2,provided in USP 23, 1995.

Test Specifications: Temperature: 37.0 ± 0.5° C. Medium: Deionizedwater, 900 mL Paddle speed 75 rpmMethod

Aliquots of medium were removed for assay after 15, 30, 45, 60, 90, 120,150, 180, 240, 300 360, 420 and 480 min, each aliquot being replacedsimultaneously by an equal volume of medium to maintain constant volume.The amount of drug substance was determined by UV spectrometry, at 272nM. The resulting dissolution profile for the tablets of Example 1 and 2are shown as FIG. 3.

in vivo Pharmacokinetic Evaluation of Formulations

The bioavailability of dosages according to the present invention wereevaluated in two human volunteer studies, Study A and Study B. Thesewere open, randomised, crossover studies in healthy volunteers. Eachdosage was administered with the aid of approximately 200 mL water, atthe start of a light breakfast and after an overnight fast. Bloodsamples were collected into tubes containing EDTA at nominal times ofpre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h after startof dosing, for assay of plasma levels of amoxicillin and clavulanate.Samples were cooled in an ice-bath awaiting further processing. Plasmawas separated by refrigerated centrifugation at 4° C. and transferred toappropriately labelled polypropylene specimen containers and storedfrozen at approximately −70° C. until assayed.

Samples were assayed for amoxicillin using a method based on proteinprecipitation with acetonitrile. Amoxicillin was extracted from humanplasma (50 μL) by means of protein precipitation, using acetonitrilecontaining the internal standard and quantified by LC/MS/MS.Specifically, human plasma (50 μL) was pipetted into a 1.5 mL Eppendorftube followed by the addition of acetonitrile containing the internalstandard ([¹³C₆]-amoxicillin, 200 μL). The tube was capped, vortex mixedand shaken for approximately 15 minutes. After centrifuging the sample(approximately 11,000×g, for 15 minutes), the supernatant wastransferred to a silanised 1.1 mL tapered autosampler vial containing200 μL of 5 mM ammonium acetate solution. An aliquot of extract wasinjected onto the HPLC/MS/MS system for analysis. The mass spectrometerwas operated in positive ion mode, employing a Turbo IonSpray interface.Multiple reaction monitoring (MRM) was used to detect the components,amoxicillin and [¹³C₆]-amoxicillin. The MRM procedure involves (1) massselection of a characteristic ion of the required drug or internalstandard in the first quadrupole mass analyser (2) fragmentation of theselected ion in the instrument's collision cell (3) detection of afragment ion which is characteristic of the compound of interest.Quantification is performed by comparison of the chromatographic peakareas of the drug relative to the area of the internal standard. Linearresponses in the analyte/internal standard peak area ratios wereobserved for analyte concentrations ranging from 0.05 pg/mL (lower limitof quantification; LLQ) to 10 μg/mL (upper limit of quantification:ULQ).

Samples were assayed for clavulanate using a method based on proteinprecipitation with acetonitrile. Clavulanate was extracted from humanplasma by means of liquid/liquid using internal standard and quantifiedby LC/MS/MS. Specifically, human plasma (50 pL) was pipetted into a 1.5mL Eppendorf tube followed by 0.2 mM ammonium acetate (200 μL) beforeaddition of acetonitrile containing the internal standard(6-aminopenicillanic acid, 400 μL). The tube was capped, vortex mixedand shaken for approximately 20 minutes. After centrifuging the sample(approximately 14,500×g, for 15 minutes), the supernatant wastransferred to a clean eppendorf tube and dichloromethane added. Afterfurther mixing and centrifugation (approximately 14, 500×g for 10minutes) supernatent (no more than 150 uL) was transferred to a tapered1.1 mL autosampler vial and left uncapped for at least 20 minutes toallow any traces of dichloromethane to evaporate. An aliquot of theextract was injected onto the HPLC/MS/MS system for analysis. The massspectrometer was operated in positive ion mode, employing a TurboIonSpray interface. Multiple reaction monitoring (MRM) was used todetect the components, clavulanate and 6-aminopenicillanic acid. The MRMprocedure involves (1) mass selection of a characteristic ion of therequired drug or internal standard in the first quadrupole mass analyser(2) fragmentation of the selected ion in the instrument's collision cell(3) detection of a fragment ion which is characteristic of the compoundof interest. Quantification is performed by comparison of thechromatographic peak areas of the drug relative to the area of theinternal standard. Linear responses in the analyte/internal standardpeak area ratios were observed for analyte concentrations ranging from0.05 μg/mL (lower limit of quantification; LLQ) to 10 μg/mL (upper limitof quantification: ULQ).

QC samples were assayed with each batch of samples against separatelyprepared calibration standards. The results of the QC samples were usedto assess the day-to-day performance of the assay.

Plasma concentration-time data for each subject in each regimen wereanalysed by non-compartmental methods using the non-compartmentalpharmacokinetic analysis program WinNonlin Professional Version 1.5. Allcalculations were based on actual sampling times. Pharmacokineticparameters determined included maximum observed plasma concentration(Cmax) and time to reach maximum plasma concentration (Tmax). Theapparent terminal elimination rate constant (lz) was derived from thelog-linear disposition phase of the concentration-time curve usinglinear least-squares regression with visual inspection of the data todetermine the appropriate number of points to calculate lz. The apparentterminal elimination half-life (T½) was calculated as ln(2)/lz.

Area under the plasma concentration-time curve from time zero to thelast quantifiable plasma concentration [AUC(0-t)] was determined usingthe linear trapezoidal rule for each incremental trapezoid and the logtrapezoidal rule for each decremental trapezoid [Chiou W L., J.Pharmacokinet. Biopharm., 1978, 6, 539-547]. The area under the plasmaconcentration-time curve extrapolated to infinity [AUC(0-inf)] wascalculated as the sum of AUC(0-t) and C(t)/lz, where C(t) was thepredicted concentration from the log-linear regression analysis at thelast measurable time point.

The time above the minimum inhibitory plasma concentration (T>MIC) wascalculated manually by graphical interpolation, where the minimuminhibitory plasma concentrations was defined as 4 ug/mL for amoxicillin.

The mean concentration-time profiles for amoxicillin and for clavulanatewere derived at each nominal sampling time for each formulation. Incases where a post-dose value was not quantifiable, a value of ½ the LLQ(0.050 ug/mL) was assigned to determine the mean value. Where thecalculated mean value was less than the LLQ or was based on greater than50% NQ values, a value of NQ was assigned for that sampling time.

Log_(e)-transformed Cmax and untransformed T>MIC for each of theformulations were analysed using Analysis of Covariance (ANCOVA) fittinga single term for formulation and fitting the data from the referenceformulation as a co-variate. The 95% confidence intervals for the meansof each formulation were constructed using the residual variance fromthe model. For Cmax, the confidence interval estimates on the log scalewere then back-transformed to obtain the 95% confidence intervals of thegeometric mean. These results were displayed graphically.

Assumptions underlying the analyses were assessed by inspection ofresidual plots. Homogeneity of variance was assessed by plotting thestudentised residuals against the predicted values from the model, whilenormality was assessed using normal probability plots. Particularattention was paid to any outlying values observed with the referenceformulation.

Study A

The first study compared three modified release dosages of 1750/125 mg(formulations I to III) and a fourth modified release dosages of1500/125 mg (formulation IV) against an immediate release dosage of1750/125 mg (formulation V), as follows:

-   -   (a) a dosage of 1750/125 mg amoxicillin/potassium clavulanate,        made up of a combination of one modified release tablet        comprising 875/125 mg amoxicillin trihydrate/clavulanate and 4%        xanthan gum and one immediate release tablet comprising 875 mg        amoxicillin trihydrate (formulation I);    -   (b) a dosage of 1750/125 mg amoxicillin/potassium clavulanate,        made up of a combination of one modified release tablet        comprising 875/125 mg crystallised sodium        amoxicillin/clavulanate and 4% xanthan gum and one immediate        release tablet comprising 875 mg amoxicillin trihydrate        (formulation II);    -   (c) a dosage of 1750/125 mg amoxicillin/potassium clavulanate,        made up of a combination of one modified release tablet        comprising 875/125 mg crystallised sodium        amoxicillin/clavulanate, citric acid (156 mg) and 2% xanthan gum        and one immediate release tablet comprising 875 mg amoxicillin        trihydrate (formulation III);    -   (d) a dosage of 1500/125 mg amoxicillin/potassium clavulanate        (made up of a modified release tablet comprising 500/125 mg        crystallised sodium amoxicillin/potassium clavulanate and two        immediate release tablet comprising 500 mg amoxicillin        trihydrate (Amoxyl, SmithKline Beecham) (formulation IV); and    -   (e) a dosage of 1750/125 mg amoxicillin/potassium clavulanate,        made up of a combination of one immediate release tablet        comprising 875/125 mg amoxicillin trihydrate/clavulanate        (Augmentin, SmithKline Beecham) and one immediate release tablet        comprising 875 mg amoxicillin trihydrate (Amoxyl, SmithKline        Beecham) (formulation V).

Results Formulation n Cmax¹ T > MIC^(1,2) AUC^(1,3) I 8 12.75 (4.96 4.5(1.8) 47.83 II 8 18.56 (4.72 4.4 (1.0) 57.46 III 8 13.03 (2.34 5.73(2.54) 54.93 IV 8 17.33 (4.66 4.8 (0.9) 56.71 V 40 20.21 (6.09 4.2 (0.9)56.33( ) standard deviation¹arithmetic mean value²T > MIC is the time (h) above an amoxicillin concentration of 4 μg/ml³Area under the curve (0 to 12 h, μg · h/mL)

The pharmacokinetic profile is shown in FIG. 4.

Study B

The second study investigated two different modified release dosages of2000/125 mg (formulations VI and VII) against an immediate releasedosage of 2000/125 mg (formulation VIII), as follows:

-   (a) a dosage of 2000/125 mg amoxicillin/potassium clavulanate, made    up of two bilayer tablets according to Example 1 (formulation VI);-   (b) a dosage of 2000/125 mg amoxicillin/potassium clavulanate, made    up of two bilayer tablets according to Example 2 (formulation VII);-   (c) a dosage of 2000/125 mg amoxicillin/potassium clavulanate, made    up of a combination of three tablets each comprising 500 mg    amoxicillin (Amoxyl, SmithKline Beecham) and one tablet comprising    500 mg amoxicillin and 125 mg potassium clavulanate (Augmentin,    SmithKline Beecham) (formulation VIII).

Results Formulation N Cmax¹ T > MIC^(1,2) T > MIC^(1,3) AUC^(1,4) VI 717.41 (1.93 6.0 (1.3) 4.8 (1.2) 74.9 VII 8 17.46 (6.02 5.9 (1.3) 4.0(1.3) 71.5 VIII 12 23.75 (5.73 4.9 (1.1) 3.5 (1.0) 69.2( ) standard deviation¹arithmetic mean value²T > MIC is the time (h) above an amoxicillin concentration of 4 μg/ml³T > MIC is the time (h) above an amoxicillin concentration of 8 μg/ml⁴Area under the curve (0 to 12 h, μg · h/mL).

Comparison of the AUC values for formulations VI and VII (bilayertablets) against VIII (immediate release tablets) shows that theabsorption of the amoxicillin component has not been compromised byformulating a part of it in a slow release layer. This means that thereis no extra, unabsorbed amoxicillin which may otherwise cause problemsfurther down in the GI tract, for instance due to a lack of absorptionand destruction of symbiotic bacteria

It was also found that for formulation VI, there was less inter-subjectvariability in the amoxicillin plasma concentrations than forformulation VII. These formulations were the same, except thatformulation VI also comprised xanthan gum (2%) in the slow releaselayer.

The pharmacokinetic profile for amoxicillin plasma concentration isshown in FIG. 5 (in which A is formulation VI, B is formulation VII, Dis formulation VIII).

The pharmacokinetic profile for the clavulanate component wassubstantially the same for the bilayer tablets and the immediate releasetablets, showing that the bioavailability thereof was not compromised byincorporation into the immediate release layer of a bilayer tablet.

Study C

In a further study, the pharmacokinetic profile of the following dosageregimens was determined:

-   (a) 2000/125 mg, using two monolith tablets of Example 5    (Formulation IX);-   (b) 2000/125 mg, using an 875 mg tablet of Example 7 in combination    with an 875 mg tablet of amoxicllin and a 250/125 mg tablet of    amoxicillin/clavulanate (Formulation X);-   (c) 2000/125 mg, using an 875 mg tablet of Example 8 in combination    with an 875 mg tablet of amoxicllin and a 250/125 mg tablet of    amoxicillin/clavulanate (Formulation XI); and-   (d) 2000/125 mg, using an 875 mg tablet of Example 9 in combination    with an 875 mg tablet of amoxicillin and a 250/125 mg tablet of    amoxicillin/clavulanate (Formulation XII).

Results Formulation N Cmax¹ T > MIC^(1,2) T > MIC³ AUC^(1,4) IX 11 20.84(8.23) 5.95 (1.23) 4.8 79.9 (26.5) X 11 18.73 (5.57) 5.14 (1.28) 3.564.8 (21.1) XI 11 18.73 (4.55) 5.47 (1.16) 3.5 69.2 (18.6) XII 11 16.67(4.04) 6.01 (1.62) 3.1 65.2 17.4)( ) standard deviation¹arithmetic mean value²T > MIC is the time (h) above an amoxicillin concentration of 4 μg/ml³T > MIC is the time (h) above an amoxicillin concentration of 8 μg/ml⁴Area under the curve (0 to 12 h, μg · h/mL).

The present invention also extends to formulations which arebioequivalent to the tablets of formulations VI and VII, in terms ofboth rate and extent of absorption, for instance as defined by the USFood and Drug Administration and discussed in the so-called “OrangeBook” (Approved Drug Products with Therapeutic Equivalence Evaluations,US Dept of Health and Human Services, 19th edn, 1999).

REFERENCE DATA

The existing Augmentin 875/125 mg tablet has a C_(max) value of 11.6±2.8μg/ml (Physicians Desk Reference, Medical Economics Co, 52 edition,1998, 2802). The time above MIC was about 40% of the 12 hour dosinginterval for an MIC of 2 μg/ml and about 30% for an MIC of 4 μg/ml(SmithKline Beecham data).

1 to
 22. (canceled)
 23. A composition comprising amoxicillin andpotassium clavulanate in a dosage of 2000 mg of amoxycillin and 125 mgof potassium clavulanate, wherein the composition is in a solid form andcomprises a first release phase and a second release phase; the firstrelease phase comprising potassium clavulanate and a first part ofamoxicillin; and the second release phase comprising a second amount ofamoxicillin in the form of a soluble salt at about 60-80% of the secondphase a pharmaceutically acceptable organic acid in a molar ratio of50:1 to 1:5 (amoxicillin to organic acid, and a reduced amount ofpharmaceutically acceptable release retarding polymer which is xanthangum at about 1-5% of the second phase; wherein the composition providesa mean maximum plasma concentration (Cmax) of amoxicillin of at least 12μg/ml. 24-68. (canceled)
 69. A composition according to claim 23 whereinthe xanthan gum is pharmaceutical grade xanthan gum, 200 mesh.
 70. Acomposition according to claim 23 wherein the amoxicillin in the firstrelease phase is amoxicillin trihydrate.
 71. A composition according toclaim 23 wherein the soluble salt of amoxicillin in the second releasephase is sodium amoxicillin.
 72. A composition according to claim 71wherein the sodium amoxicillin is crystallized sodium amoxicillin.
 73. Acomposition according to claim 23 wherein the composition provides anArea under the Curve (AUC) value of amoxicillin which is at least 80% ofthat of the same amount if taken as an immediate release formulationover the same dosage period.
 74. A composition according to claim 23wherein the composition provides a mean plasma concentration ofamoxicillin of at least 4 μg/ml for at least 4.4 hours
 75. A compositionaccording to claim 23 wherein the ratio of amoxicillin in the first andsecond release phases is from 3:1 to 1:3.
 76. A composition according toclaim 23 wherein the ratio of amoxicillin in the first and secondrelease phases is from 3:1 to 2:3.
 77. A composition according to claim23 wherein the ratio of amoxicillin in the first and second releasephases is from 2:1 to 2:3.
 78. A composition according to claim 23wherein the ratio of amoxicillin in the first and second release phasesis from 3:2 to 1:1.
 79. A composition according to claim 23 wherein thesolid form is a tablet.
 80. A composition according to claim 79 whereinthe tablet is a bilayer tablet.
 81. A composition according to claim 23wherein the first release phase comprises essentially all the potassiumclavulanate.
 82. A composition according to claim 23 wherein the releaseof amoxicillin has a biphasic profile.
 83. A method for treating abacterial infection in a patient in need thereof comprisingadministering to said patient an effective amount of a formulationaccording to claim
 23. 84. A method according to claim 83 in which thebacterial infection is caused by at least one of the organisms S.pneumoniae, H. influenzae, and M. catarrhalis.
 85. A method according toclaim 84 wherein the S. pneumoniae are Drug Resistant S. pneumoniae andPenicillin Resistant S. pneumoniae organisms.
 86. A method according toclaim 83 wherein the bacterial infection is a respiratory tractinfection.
 87. A method according to claim 86 wherein the respiratorytract infection is community acquired pneumoniae (CAP), acuteexacerbation of chronic bronchitis (AECB), or acute bacterial sinusitis(ABS).
 88. A method according to claim 83 wherein the formulation isadministered over 7 to 14 days.
 89. The composition of claim 23 whereinthe pharmaceutically acceptable organic acid is in a molar ratio of 20:1to 1:2 (amoxicillin to organic acid).
 90. The composition of claim 23wherein the pharmaceutically acceptable organic acid is selected frommono-carboxylic acids and poly-carboxylic acids having from 2 to 25carbon atoms, monocyclic and polycyclic aryl acids, and monohydrogen,dihydrogen metal salts of multi-valent acids.
 91. The composition ofclaim 90 wherein the pharmaceutically acceptable organic acid isselected from malonic acid, succinic acid, fumaric acid, maleic acid,adipic acid, lactic acid, levulinic acid, sorbic acid, or a fruit acidsuch as tartaric acid, malic acid, ascorbic acid, and citric acid. 92.The composition of claim 91 wherein the pharmaceutically acceptableorganic acid is citric acid.
 93. The composition of claim 92 wherein thesodium amoxicillin and citric acid are in a molar ratio of 20:1 to 1:2.94. The composition of claim 93 wherein the sodium amoxicillin is about438 mg±5%, citric acid is about 78 mg±10%, and xanthan gum is about 2%by weight.